Cancer affects approximately 10 million people globally and it is expected to increase to 15 million by 2020. Worldwide approximately 23 million people are living with cancer and about 5.2 million people die. Breast and lung cancer account for 25% of cancer incidences.
Expression of Human Epidermal growth factor receptor 2 (or “Her2”) in breast cancer, prostate cancer, lung cancer, gastric cancer and the like has been reported and Her2 is considered to be involved in the growth of these cancers. For example, Slamon et al., Science 235, 177 (1987) demonstrated that about 30% of primary human breast carcinoma tumors contained an amplified Her2 gene. More recently, it has been reported that about 25% of primary prostate cancer is Her2 expression positive, and the percentage increases along with the progression of the cancer (Journal of the National Cancer Institute, Vol. 92, No. 23, pp. 1918-1925 (2000)). Similarly, 4-27% of lung cancer cases are reported to overexpress Her2/neu (ErbB2). Overexpression of HER2/neu and other erbB receptors is associated with increased disease recurrence and leads to a poor prognosis in such cancers.
Many other diseased states are also characterized by the uncontrolled reproduction of cells. These diseased states involve a variety of cell types and, in addition to leukemia and cancer, include psoriasis, atherosclerosis and restenosis injuries. The inhibition of tyrosine kinase is believed to have utility in the control of uncontrolled cellular reproduction, i.e., cellular proliferative disorders
Her2 is also known as neu, ErbB-2, or ERBB2. Her2/neu (ErbB2), a member of the type I transmembrane receptor tyrosine kinase family, regulates cell differentiation and growth during embryogenesis and breast development. This oncogene was first obtained from rat neuroglioblastoma induced by a chemical carcinogenic substance was found to encode a protein belonging to the EGF receptor family, and the relationship with which was suggested. Thereafter, an neu human homologue was isolated and named as ERBB2 or Her2 based on the similarity to an EGF receptor, ERBB (avian erythroblastosis oncogene B). The oncogene later found to code for EGFR (Epidermal Growth Factor Receptor). Gene cloning subsequently determined that neu, Her2, and erbB2 are species variants of one another. (Slamon, D. J., et al., Science, 235:177 182, 1987).
ErbB receptors or epidermal growth factor receptors (EGFR) play an important role in a variety of signal transduction pathways that promote cell differentiation, growth, proliferation, and migration. Interaction between Erb receptors allows ErbB2/Her2 to participate in effective signaling. In particular, EGFR and Her2 have been implicated in the development of human cancer, hence Her2 represents an attractive therapeutic target against Her2 positive cancers.
Her2 is a cell membrane surface bound receptor tyrosine kinase, normally involved in the signal transduction pathways leading to cell proliferation, differentiation, and migration. Co-expression of Her2/neu and other members of erbB in normal cells promotes formation of dimer complexes, which cause malignant cell transformation. Olayioye MA (2001). “Update on Her-2 as a target for cancer therapy: intracellular signaling pathways of ErbB2/Her-2 and family members,” Breast Cancer Res. 3(6): 385-389.
Her2 hardly expresses in normal tissues. Therefore, an Her2 selective therapeutic drug would be cancer selective, with the reduced toxicity or extremely few side effects. This means that an extreme safe and highly versatile treatment method could be provided, which is strikingly different from conventional cancer chemotherapeutic agents.
Currently, the only drugs that can disable both Her2 and EGFr function (Trastuzumab or Herceptin, Pertuzumab, and similar humanized monoclonal antibodies) are targeted to receptor tyrosine kinase in the cytoplasmic domains. Small molecule tyrosine kinase inhibitors such as the quinazolinamine, Lapatinib (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2-furyl]quinazolin-4-amine), which compete for ATP binding sites on the tyrosine kinase domain of receptors are also being used to treat Her2 positive tumors.

Attempts have also been made to identify other small molecules which act as tyrosine kinase inhibitors, and other compounds inhibiting a receptor-type tyrosine kinase (including Her2/EGFR kinase) include fused heterocyclic compounds such as compounds generally depicted as
(see, for example, WO97/13771, WO98/02437, WO00/44728, U.S. Pat. No. 6,596,878, US 2005/0148607, and US 2008/0214584), quinazoline derivatives such as compounds generally depicted as
(see, for example, WO02/02552, WO01/98277, WO03/049740 and WO03/050108, U.S. Pat. No. 6,596,878), thienopyrimidine derivatives such as compounds generally depicted as
(see, for example, WO03/053446, U.S. Pat. No. 7,300,935), thienyl derivatives such as compounds generally depicted as
(see for example, U.S. Pat. No. 5,710,173), aromatic azole derivatives such as compounds generally depicted as
(see, for example, WO01/77107, WO03/031442, U.S. Pat. Nos. 6,716,863 and 6,984,653), and the like are known.
Further, bis monocyclic, bicyclic or heterocyclic aryl compounds such as compounds generally depicted as
(see, for example, WO 92/20642), vinylene-azaindole derivatives such as compounds generally depicted as
(see, for example, WO94/14808), azaindoles such as compounds generally depicted as
(see, for example, WO03/000688 and WO96/000226) and 1-cyclopropyl-4-pyridyl-quinolones such as compounds generally depicted as
(see, for example, U.S. Pat. No. 5,330,992) have been described generally as tyrosine kinase inhibitors. Styryl compounds such as compounds generally depicted as
(see, for example, U.S. Pat. Nos. 5,217,999, 5,596,878), styryl-substituted pyridyl compounds such as compounds generally depicted as
(see, for example, U.S. Pat. No. 5,302,606), tyrphostin-like compounds such as compounds generally depicted as
(see, for example, U.S. Pat. No. 6,225,346), seleoindoles and selenides such as compounds generally depicted as
(see, for example, WO94/03427), 1H-pyrrolo[2,3-b]pyridines such as compounds generally depicted as
(see, for example, WO01/098299), tricyclic polyhydroxylic compounds such as compounds generally depicted as
(see, for example, WO92/21660), 2-pyrazolin-5-ones such as compounds generally depicted as
(see, for example, WO 01/01921), and benzylphosphonic acid compounds such as compounds generally depicted as
(see, for example, WO91/15495) have been described as compounds for use as tyrosine kinase inhibitors for use in the treatment of cancer.
While drugs targeted to the receptor-type tyrosine kinase enzyme have shown promise in treating some cancers, the concern remains that chronic use of such agents that depend on tyrosine kinase domain receptors may lead to acquired resistance in patients. Indeed, such resistance may be seen within 12 months of the treatment with such agents. It is believed that these reflect the fact that kinase domains can alter their structure and become resistant over regular use. Beyond this, the structure of kinase domain is ubiquitous and highly conserved and long use of kinase inhibitors can inhibit other kinases involved in the development of cells/organs. Thus, these kinase domain targeted drugs may be unsuitable for small children with cancers.